ANTIGEN PROCESSING AND PRESENTATION Prof. Anand Prakash

Department of Biotechnology Mahatma Gandhi Central University

Motihari Bihar

T cells recognise processed peptides displayed with Histocompatibility Complex class I (MHC-I) and class II (MHC-II) molecules. Processed peptides from pathogens or transformed cells are displayed with MHC-I and MHC-II. Processed peptides from self antigens are presented with MHC-I. Two pathways for antigen processing and presentation are: Endogenous pathway Exogenous Pathway

Endocytic or exogenous processing pathway MHC II binds peptides and present to CD4_ T Cells

Cytosolic or endogenous processing pathway MHC I binds peptides and present to CD8+ T Cells

ANTIGEN PROCESSING AND PRESENTATION

Uptake: Self antigens and pathogens are accessed and taken up by intracellular pathways of degradation.

Degradation: Controlled processing of antigens to peptides through proteolysis.

Peptide: MHC Complex Formation: Loading of the processed peptides onto MHC molecules.

Presentation of the Peptide: MHC Complex: Movement of MHC: Peptide Complexes on surface of cells for recognition by T-Cells.

B-Cells recognize variety of antigens Proteins Polysaccharides Lipids Nucleic acids

T-Cells recognize only protein antigens which are displayed in antigen binding cleft of MHC.

Antigen presentation is a decisive step in the adaptive immune response It permits self/non self discrimination by T-cells, eventually facilitating the recognition of pathogens.

1. Virus/parasite infects cell

2. MHCI binds processed antigen

3. Presentation

4. Recognition

5. Activation and proliferation 6. Induction of cell death

Peptide binding cleft

α1 α2

Β2 microglobulin α3, interacts

With CD8+

Trans membrane region

N N

C

C

Processed Endogenous antigen

Extracellular live and replicate outside host cells and endocytosed by macrophages and dendritic cells, processed and presented with MHCII.

Microbe MHC-II Processed Exogenous antigen

Process by which pathogens or their products are degraded to process peptide antigens is known as ANTIGEN PROCESSING These peptide fragments bind with MHC molecules inside the cell The MHC peptide complex thus formed displays the processed peptide antigen and this is known as ANTIGEN PRESENTATION

How peptide fragments from pathogens and their products are produced How these processed peptide antigens are combined with MHC How MHC: peptide complex is processed to the T-Cells

PROCESSING & PRESENTATION OF INTRACELLULAR OR ENDOGENOUS ANTIGENS

PROCESSING & PRESENTATION OF INTRACELLULAR ANTIGENS Endogenous proteins are presented by MHC-I. Cytosolic or endogenous proteins move to the proteasome complex and get processed into short peptides. These short peptides then move into ER via TAP for display with MHC-I.

α-chain assemble with β2m to form MHC-I in the presence the chaperone calnexin (CNX) in ER. Peptides after proteasomal degradation of endogenous proteins enter ER via TAP. Peptides longer than the 8-10 residues undergo trimming by ER amino-peptidases known as ERAAP/ERAP1 and ERAP2. Peptides having high affinity and of right size complex with MHC-I by a tapasin-mediated editing process. MHC-I-peptide complexes move to the cell surface.

2. Viral Proteins are synthesized in the host cell 3. Viral Proteins are digested in the proteasome and processed in the cytosol 4. TAP Transporters associated with antigen processing) consists of TAP-1 and TAP-2

5. Peptides transported from cytosol to endoplasmic reticulum and bind to newly synthesized MHC-I 6. MHC-I peptide complex moves to the cell surface via Golgi apparatus

1. Viral Nucleic acid enters host cell 1

2

3 4

5

6

Target cell normally presents self antigens with MHC-I Under infection by an intracellular pathogen presents processed antigen with MHC-I

Cytotoxic T-Cells bearing TCR along with CD8+ co-receptor. It recognizes the processed peptide presented in the antigen binding cleft of the MCH-I

PROCESSING AND PRESENTATION OF EXTRACELLULAR OR EXOGENOUS ANTIGENS

PROCESSING AND PRESENTATION OF EXTRACELLULAR ANTIGEN Exogenous proteins are presented by MHC-II. Antigens after phagocytosis/ macropinocytosis/ endocytosis, move to late endosome and after further processing are presented with MHC-II. Cytoplasmic/nuclear antigens after autophagy are processed and presented with MHC-II molecules.

Present peptides derived from extracellular or exogenous antigens B-Cell Macrophage Dendritic Cell

TYPICAL APCs

Nature Reviews Immunology

Phagocytic. Found in T-Cell zone of Lymph node. Express MHC II constitutively and have antigen processing pathway. Express co-stimulatory molecules once activated.

Internalize antigens through B-Cell Receptor. Express MHC II constitutively and have antigen processing. Express co-stimulatory molecules once activated.

Nature Reviews Immunology

ATYPICAL APCs

Have inducible MHC-II Antigen presentation limited to specific immune environments. No t confimed whether they can activate T-Helper Cells.

Extracellular Pathogen is recognized Phagocytosed Endocytosed

ANTIGENIC PEPTIDE BINDING TO MHC-II MHC-II associate with Invariant Chain (I chain) and move to mature endosomes via TGN or from the cell surface after recycling. Within endosomes, I chain is sequentially proteolyzed to residual I chain fragment, CLIP (class II-associated invariant chain peptide ). Subsequent removal of CLIP ; MHC-II loaded with antigenic peptides. Antigens delivered to late endosomes by phagocytosis, pinocytosis, endocytosis, and autophagy, are Processed by cathepsins and the thiol oxidoreductase ,GILT. The MHC-II-peptide complexes are subsequently transported to the cell surface .

TH cell CD4 co-receptor TCR

APC cells display the processed peptide in the Antigen Binding Cleft of the MHC-II T Helper Cells recognize the Antigen displayed in the MHC-II with the TCR and co-receptor CD4.

• Antigen Presentation, In Immunology Guidebook, 2004. • Antigen Processing and Presentation, Zoltan A. Nagy, in A History of Modern Immunology, 2014. • Immunity and Resistance to Viruses, Susan Payne, in Viruses, 2017. • Adaptive Immune Responses to Infection, The Major Histocompatibility Complex (MHC) and Antigen Presentation, Christopher J. Burrell, ... Frederick A. Murphy, in Fenner and White's Medical Virology (Fifth Edition), 2017.

To be continued…